The invention disclosed herein concerns a process of making 2-aryl carbapenems. Carbapenem antibiotics, particularly thienamycin and imipenem (see U.S. Pat. Nos. 3,950,377 and 4,194,047) are two non-aryl substituted carbapenems which are well known for treating gram-negative and gram-positive bacterial infections. Active 2-aryl substituted carbapenems include those disclosed in U.S. Pat. Nos. 5,034,384 and 5,011,832.
As is generally appreciated, the carbapenem nucleus is unstable, thus necessitating mild coupling reagents. One alternative procedure utilizes stannane reagents which may introduce toxic impurities into the reaction medium, making purification of the product and subsequent processing difficult. See, e.g., Rano et al. Tetrahedron Letters 1990, 2853.
Related couplings with .beta.-lactam containing substrates are given by Monroe and McDonald (Journal of Organic Chemistry 1989, 54, 5828), Kant (Tetrahedron Letters 1990, 3389), and Farina (Tetrahedron Letters 1988, 5739, 6043).
Boronic acid or ester couplings were reported by Snieckus (Tetrahedron Letters 1990, 1665), Suzuki (Chem. Letters 1989, 1405; Journal of the American Chemical Society 1985, 107, 972).
The boronic acid coupling methodology disclosed herein presents mild conditions, low toxicity and ease of product purification, such as those set forth in copending U.S. patent application No. 07/978,598 filed on Nov. 19, 1992. The present case contains unexpected improvements in the boronic acid-carbapenem reaction described therein.
Selected examples of the generalized palladium catalyzed coupling of organometallic agents with enol triflates are reported by Scott and McMurry (Accounts of Chemical Research, 1988, 21, 47), Stille (Angew. Chem International Edition English, 1986, 25, 508) and Piers (Tetrahedron Letters 1991, 4555).